Cancer is a leading cause of death in the United States. For example in 1998, an estimated 185,000 men were diagnosed with prostate cancer, and more than 39,000 men died of the disease. See, S. H. Landis et al., CA Cancer J. Clin. 48, 6, 1998. Although survival rates for cancer patients are good in patients that are diagnosed early, the treatment usually used for cancer is often indiscriminant attacking both normal cells and cancerous cells. Cytotoxic agents (chemotherapy) or radiation therapy are commonly used treatments for cancer. For example, despite modern advances in focusing external beam radiation to the tumor mass, some normal tissues are usually included in the radiation field.
Cytotoxic agents and radiation can kill both normal and malignant tissues, primarily by triggering apoptosis. Chemoprevention of cell death is an important goal for pharmacologic intervention in a variety of clinical settings, including ischemia and side effects from cancer treatment. Drugs that inhibit apoptosis in normal cells/tissues within the treatment area are of great value. Pharmacologic agents that have been used to protect cells from ionizing radiation fall into three major categories. First, sulfhydryl containing agents, metal chelators, and various anti-oxidants, which can inhibit the propagation of free radical reactions. Second, exogenous growth and survival factors, which can stimulate the endogenous synthesis of cell-protective molecules. Third, chemical inhibitors of essential proteins in the apoptosis cascade, which can delay cell suicide until the damage is repaired.
Recently, a small molecule, 2-(2-imino-4,5,6,7-tetrahydro-benzothiazol-3-yl)-1-p-tolyl-ethanone hydrobromide, 1, was identified from a broad screen of 10,000 compounds in an assay that assessed the ability to inhibit cell death from γ-radiation (See Komarov, P. G., et al. Science, 285:1733-1737, 1999.) This compound was designated pifithrin-α, (PFTα, PFT-alpha).
This compound has been shown to protect normal cells from the lethal effects of some cancer treatments. For example, cells pre-incubated with PFTα, and then exposed to γ-radiation, showed a decreased in apoptosis. PFTα also reduced mortality after γ-radiation of mice.
In addition, there are other causes of cell death such as, for example, ischemia. The ischemia can be caused by several sources such as, stroke, heart attack and traumas.
Currently, there is a need for novel, potent, and selective agents to selectively protect against unintentional cell death or tissue damage, caused by cancer treatment and from other side effects of cancer treatment such as, oral mucositis, hair loss, diarrhea due to damage to the gastrointestinal epithelium, and myelosuppression.